The studies in the laboratory have focused on two broad areas: signal transduction involving low molecular weight GTPases such as Ras and Rap1, and the role of tumor suppressor genes in cell growth regulation and tumorigenesis. As a focus for these studies, we have been investigating the molecular pathology of two human genetic diseases: neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). Both conditions predispose affected individuals to the development of benign tumors in a wide variety of organs, and more rarely to malignant tumors. In the NF1 studes, we have found that normal Schwann cell growth is regulated through an interaction of the cyclic AMP (cAMP) pathway and the neuregulin/tyrosine kinase receptor pathway. Specifically, we found that stimulation of Schwann cells with glial growth factor (GGF) increased the level of intracellular cAMP. Furthermore, in contrast to fibroblasts, activation of the cAMP-dependent protein kinase (PK-A) did not block the Ras/Raf-1/MAP kinase pathway in Schwann cells. The product of the tuberous sclerosis-2 gene (TSC2), designated tuberin, interacts with the low molecular weight GTPase Rap1, and may regulate its activity by stimulating the GTPase activity of this protein. We have shown that there is a significant degree of overlap in the intracellular localization of these proteins, and in their staining patterns in tissues that are affected in patients with TSC, such as the kidney and brain. Furthermore, we have found that a significant proportion of non- TSC brain tumors show a reduction or loss of tuberin expression, suggesting that TSC2 may also function as a tumor suppressor in sporadic human tumors. Currently, we are conducting a structure/function analysis of TSC2, using a combination of site-directed and naturally occuring mutants to study the effect of these mutant TSC2 products on cell growth, as well as in assays of the biochemical function and intracellular localization of tuberin.